Prior to metastasis tumor cells undergo epithelial-mesenchymal transition (EMT), resulting in increased invasive potential and drug resistance. We have identified human TopoIIa as an enhancer protein required for TCF/Lef/�-catenin (TCF) transcription, implicated in 80% of sporadic colorectal cancer (CRC), and familial adenomatous polyposis (FAP). This presentation will discuss our recent research demonstrating that when TopoIIa participates in protein-complexes, binding sites accommodating TopoIIa poisons are hindered/altered causing drug resistance. An Achilles heel to this mechanism of drug resistance is the requirement of ATP for TopoIIa complex formations. Using innovative 3D-models of metastatic cancer we identified neoamphimedine (neo), a marine alkaloid that can revert/suppress the metastatic phenotype through ATP-competitive inhibition of TopoIIa, ultimately blocking aberrant TCF-transcription and subsequent invasive potential. Finally, we will discuss the development of neo as an anti-metastatic agent with the potential to eradicate mortality due to metastasis and increase the quality of life by decreasing adverse side effects.

Topoisomerase IIα mediated drug resistance in metastatic cancer: An old target with new tricks

245th National Meeting (2013)

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